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The Fbw7 (F-box/WD repeat-containing protein 7) ubiquitin ligase targets multiple oncoproteins for degradation and is commonly mutated in cancers. Like other pleiotropic tumor suppressors, Fbw7's complex biology has impeded our understanding of how Fbw7 mutations promote tumorigenesis and hindered the development of targeted therapies. To address these needs, we employed a transfer learning approach to derive gene-expression signatures from The Cancer Gene Atlas datasets that predict Fbw7 mutational status across tumor types and identified the pathways enriched within these signatures. Genes involved in mitochondrial function were highly enriched in pan-cancer signatures that predict Fbw7 mutations. Studies in isogenic colorectal cancer cell lines that differed in Fbw7 mutational status confirmed that Fbw7 mutations increase mitochondrial gene expression. Surprisingly, Fbw7 mutations shifted cellular metabolism toward oxidative phosphorylation and caused context-specific metabolic vulnerabilities. Our approach revealed unexpected metabolic reprogramming and possible therapeutic targets in Fbw7-mutant cancers and provides a framework to study other complex, oncogenic mutations., Competing Interests: The authors declare no conflict of interest.

Mammalian skeletal muscle is broadly characterized by the presence of two distinct categories of muscle fibers called type I "red" slow twitch and type II "white" fast twitch, which display marked differences in contraction strength, metabolic strategies, and susceptibility to fatigue. The relative representation of each fiber type can have major influences on susceptibility to obesity, diabetes, and muscular dystrophies. However, the molecular factors controlling fiber type specification remain incompletely defined. In this study, we describe the control of fiber type specification and susceptibility to metabolic disease by folliculin interacting protein-1 (Fnip1). Using Fnip1 null mice, we found that loss of Fnip1 increased the representation of type I fibers characterized by increased myoglobin, slow twitch markers [myosin heavy chain 7 (MyH7), succinate dehydrogenase, troponin I 1, troponin C1, troponin T1], capillary density, and mitochondria number. Cultured Fnip1-null muscle fibers had higher oxidative capacity, and isolated Fnip1-null skeletal muscles were more resistant to postcontraction fatigue relative to WT skeletal muscles. Biochemical analyses revealed increased activation of the metabolic sensor AMP kinase (AMPK), and increased expression of the AMPK-target and transcriptional coactivator PGC1α in Fnip1 null skeletal muscle. Genetic disruption of PGC1α rescued normal levels of type I fiber markers MyH7 and myoglobin in Fnip1-null mice. Remarkably, loss of Fnip1 profoundly mitigated muscle damage in a murine model of Duchenne muscular dystrophy. These results indicate that Fnip1 controls skeletal muscle fiber type specification and warrant further study to determine whether inhibition of Fnip1 has therapeutic potential in muscular dystrophy diseases.

Kaposi's sarcoma (KS) is the most commonly reported tumor in parts of Africa and is the most common tumor of AIDS patients world-wide. KS-associated herpesvirus (KSHV) is the etiologic agent of KS. Although KS tumors contain many cell types, the predominant cell is the spindle cell, a cell of endothelial origin that maintains KSHV latency. KSHV activates many cell-signaling pathways but little is known about how KSHV alters cellular metabolism during latency. The Warburg effect, a common metabolic alteration of most tumor cells, is defined by an increase in aerobic glycolysis and a decrease in oxidative phosphorylation as an energy source. The Warburg effect adapts cells to tumor environments and is necessary for the survival of tumor cells. During latent infection of endothelial cells, KSHV induces aerobic glycolysis and lactic acid production while decreasing oxygen consumption, thereby inducing the Warburg effect. Inhibitors of glycolysis selectively induce apoptosis in KSHV-infected endothelial cells but not their uninfected counterparts. Therefore, similar to cancer cells, the Warburg effect is necessary for maintaining KSHV latently infected cells. We propose that KSHV induction of the Warburg effect adapts infected cells to tumor microenvironments, aiding the seeding of KS tumors. Additionally, inhibitors of glycolysis may provide a unique treatment strategy for latent KSHV infection and ultimately KS tumors.

The BCL2 protooncogene encodes an inner mitochondrial membrane protein that blocks programmed cell death. BCL2 was isolated from the chromosomal breakpoint of follicular B-cell lymphoma. Transgenic mice that overexpress BCL2 display extended survival of resting B cells. In this study we use a monospecific anti-human BCL2 antibody to define the distribution of BCL2 protein within organized tissues. BCL2 is restricted within germinal centers to the follicular mantle and to portions of the light zone implicated in the selection and maintenance of plasma cells and memory B cells. BCL2 is present in the surviving T cells in the thymic medulla. All hematopoietic lineages that derive from a renewing stem cell also display BCL2. A limited number of nonlymphoid tissues demonstrate BCL2 and can be grouped as (i) glandular epithelium in which hormones or growth factors regulate hyperplasia and involution, (ii) complex differentiating epithelium such as skin and intestine characterized by long-lived stem cells, and (iii) long-lived postmitotic cells such as neurons. Within these tissues that demonstrate apoptotic cell turnover, BCL2 is often topographically restricted to long-lived or proliferating cell zones. BCL2's function as an antidote to apoptosis may confer longevity to progenitor and effector cells in these tissues.

Fractions of porcine cerebral cortex extract separated by molecular weight on a Sephadex G-75 column were tested for their activities and potencies to inhibit [3H]benzodiazepine binding to rat brain homogenates. The fractions spanned molecular weights from 500 to 100,000. A potent inhibitor (benzodiazepine-competitive factor I, BCF-I) was discovered in the fraction containing substances with molecular weights from 40,000 to 70,000. Equilibrium binding studies indicated that BCF-I was a competitive inhibitor, making it a candidate as a benzodiazepine endogenous factor or profactor. BCF-I was heat stable, but trypsin digestion destroyed its activity. Another inhibitory fraction (BCF-II) was 1/5th as active as BCF-I and contained substances with molecular weights from 1000 to 2000.